2-46917490-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001288953.2(TTC7A):c.82+213A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0593 in 152,186 control chromosomes in the GnomAD database, including 459 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.059 (459 hom., cov: 32)
• Consequence: TTC7A NM_001288953.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.847

Genes affected

MCFD2 (HGNC:18451): (multiple coagulation factor deficiency 2, ER cargo receptor complex subunit) This gene encodes a soluble luminal protein with two calmodulin-like EF-hand motifs at its C-terminus. This protein forms a complex with LMAN1 (lectin mannose binding protein 1; also known as ERGIC-53) that facilitates the transport of coagulation factors V (FV) and VIII (FVIII) from the endoplasmic reticulum to the Golgi apparatus via an endoplasmic reticulum Golgi intermediate compartment (ERGIC). Mutations in this gene cause combined deficiency of FV and FVIII (F5F8D); a rare autosomal recessive bleeding disorder characterized by mild to moderate bleeding and coordinate reduction in plasma FV and FVIII levels. This protein has also been shown to maintain stem cell potential in adult central nervous system and is a marker for testicular germ cell tumors. The 3' UTR of this gene contains a transposon-like human repeat element named 'THE 1'. A processed RNA pseudogene of this gene is on chromosome 6p22.1. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Apr 2016]

TTC7A (HGNC:19750): (tetratricopeptide repeat domain 7A) This gene encodes a protein containing tetratricopeptide repeats. Mutations in this gene disrupt intestinal development and can cause early onset inflammatory bowel disease and intestinal atresia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 2-46917490-A-G is Benign according to our data. Variant chr2-46917490-A-G is described in ClinVar as [Benign]. Clinvar id is 1285856.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.122 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCFD2	NM_001171508.2	c.-6-8313T>C		intron_variant
MCFD2	NM_001171511.3	c.93-9521T>C		intron_variant
TTC7A	NM_001288953.2	c.82+213A>G		intron_variant
TTC7A	XM_047445148.1	c.-81+913A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCFD2	ENST00000409147.1	c.-7-9521T>C		intron_variant		2
MCFD2	ENST00000409207.5	c.-6-8313T>C		intron_variant		2		P1
TTC7A	ENST00000409245.5	c.82+213A>G		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.0592 AC: 9000 AN: 152068 Hom.: 456 Cov.: 32

Gnomad AFR AF: 0.125

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0817

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.0937

Gnomad SAS AF: 0.0520

Gnomad FIN AF: 0.0424

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0188

Gnomad OTH AF: 0.0435

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0593 AC: 9028 AN: 152186 Hom.: 459 Cov.: 32 AF XY: 0.0610 AC XY: 4536 AN XY: 74402

Gnomad4 AFR AF: 0.125

Gnomad4 AMR AF: 0.0815

Gnomad4 ASJ AF: 0.00260

Gnomad4 EAS AF: 0.0941

Gnomad4 SAS AF: 0.0522

Gnomad4 FIN AF: 0.0424

Gnomad4 NFE AF: 0.0188

Gnomad4 OTH AF: 0.0425

Alfa AF: 0.0178 Hom.: 18

Bravo AF: 0.0664

Asia WGS AF: 0.0850 AC: 296 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 06, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.26
Dann	Benign	0.65

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs6729120; hg19: chr2-47144629; COSMIC: COSV60177817; COSMIC: COSV60177817;